Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma.
Infantile hemangiomas are localized and rapidly growing regions of disorganized angiogenesis. We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls. Low VEGFR1 expression in hemECs results in VEGF-dependent activation of VEGFR2 and downstream signaling pathways. In hemECs, transcription of the gene encoding VEGFR1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT). Low VEGFR1 expression in hemECs is caused by reduced activity of a pathway involving beta1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2 and NFAT. In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2 (KDR) and TEM8 (ANTXR1). These mutations result in increased interactions among VEGFR2, TEM8 and beta1 integrin proteins and in inhibition of integrin activity. Normalization of the constitutive VEGFR2 signaling in hemECs with soluble VEGFR1 or antibodies that neutralize VEGF or stimulate beta1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.
Jinnin
Masatoshi
M
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
Medici
Damian
D
Park
Lucy
L
Limaye
Nisha
N
Liu
Yanqiu
Y
Boscolo
Elisa
E
Bischoff
Joyce
J
Vikkula
Miikka
M
Boye
Eileen
E
Olsen
Bjorn R
BR
D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000201:enzymology; D005260:Female; D006391:Hemangioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D039641:Integrin beta Chains / Q000378:metabolism; D008840:Microfilament Proteins; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
C473287:ANTXR1 protein, human; D039641:Integrin beta Chains; D008840:Microfilament Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2